Dopamine D1 receptor activation improves PCP-induced performance disruption in the 5C-CPT by reducing inappropriate responding.

Attentional deficits contribute significantly to the functional disability of schizophrenia patients. The 5-choice continuous performance test (5C-CPT) measures attention in mice, rats, and humans, requiring the discrimination of trial types that either require a response or the inhibition of a response. The 5C-CPT, one version of human continuous performance tests (CPT), enables attentional testing in rodents in a manner consistent with humans. Augmenting the prefrontal cortical dopaminergic system has been proposed as a therapeutic target to attenuate the cognitive disturbances associated with schizophrenia. Using translational behavioural tasks in conjunction with inducing conditions relevant to schizophrenia pathophysiology enable the assessment of pro-attentive properties of compounds that augment dopaminergic activity. Here, using a repeated phencyclidine (PCP) treatment regimen and the 5C-CPT paradigm, we assess the pro-attentive properties of SKF 38393, a dopamine D1 receptor agonist, in rats. We show that repeated PCP treatment induces robust deficits in 5C-CPT performance indicative of impaired attention. Pre-treatment with SKF 38393 partially attenuates the PCP-induced deficits in 5C-CPT performance by reducing false alarm responding and increasing response accuracy. Impaired target detection was still evident in SKF 38393-treated rats however. Thus, augmentation of the dopamine D1 system improves PCP-induces deficits in 5C-CPT performance by selectively reducing aspects of inappropriate responding. These findings provide evidence to support the hypothesis that novel therapies targeting the dopamine D1 receptor system could improve aspects of attentional deficits in schizophrenia patients.

Characterisation of amyloid-induced inflammatory responses in the rat retina.

Amyloid-induced inflammation is thought to play a critical and early role in the pathophysiology of Alzheimer's disease. As such, robust models with relevant and accessible compartments that provide a means of assessing anti-inflammatory agents are essential for the development of therapeutic agents. In the present work, we have characterised the induction of inflammation in the rat retina following intravitreal administration of amyloid-beta protein (Aß). Histology and mRNA endpoints in the retina demonstrate Aß1-42-, but not Aß42-1-, induced inflammatory responses characterised by increases in markers for microglia and astrocytes (ionised calcium-binding adaptor molecule 1 (iba-1), GFAP and nestin) and increases in mRNA for inflammatory cytokines and chemokines such as IL1-ß, MIP1α and TNFα. Likewise, analysis of vitreal cytokines also revealed increases in inflammatory cytokines and chemokines, including IL1-ß, MIP1α and MCP1, induced by Aß1-42 but not Aß42-1. This profile of pro-inflammatory gene and protein expression is consistent with that observed in the Alzheimer's disease brain and suggest that this preclinical model may provide a useful relevant tool in the development of anti-inflammatory approaches directed towards Alzheimer's disease therapy.

The construction of multi-factor crossover designs in animal husbandry studies.

For ethical reasons it is important to try to obtain as much useful information as possible from an animal experiment whilst minimizing the number of animals used. Crossover designs, where applicable, provide an ideal framework for achieving this. If two or more treatment factors are included in the crossover design then the reduction in total animal usage can be considerable. In this paper we consider such designs, defined as multi-factor crossover designs. The designs are applicable when there are several different treatment factors, each at t levels, to be applied to the experimental units. The motivation for investigating these designs was a study conducted at GlaxoSmithKline to determine the preference of male and female dogs for t=5 different types of bed and t=5 different bedding conditions. A construction method is given for forming universally optimal designs for t not too large. Also given is an example for the special case where the number of treatment levels t=6.